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Link to relevant study record(s)

Description of key information

No studies are available. The molecular weight, physicochemical properties incl. water solubility and octanol-water partition coefficient of the substance suggest that oral, inhalative and dermal absorption occur. Widely distribution within the water compartment of the body after systemic absorption is because of lipophilicity of the test substance not expected. However, the distribution into cells particularly in fatty tissues is likely. Based on its log Pow the test substance is considered to accumulate. The test substance might be metabolized after absorption.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
Absorption rate - dermal (%):
Absorption rate - inhalation (%):

Additional information

In accordance with Annex VIII, Column 1, Item 8.8 of Regulation (EC) No 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2014), assessment of the toxicokinetic behaviour of the test substance was conducted to the extent that can be derived from the relevant available information on physicochemical and toxicological characteristics. There are no studies available evaluating the toxicokinetic properties of the substance.


The test substance is a colourless to pale yellow clear liquid with a molecular weight of 184.3 g/mol and a slightly water solubility of 21 mg/L at 20°C. The substance has a low vapour pressure of 36.87 Pa at 20°C and the log Pow is 4.4 at 40°C.



The major routes by which the test substance can enter the body are via the lung, the gastrointestinal tract, and the skin. To be absorbed, the test substances must transverse across biological membranes either by active transport mechanisms or - as being the case for most compounds - by passive diffusion. The latter is dependent on compound properties such as molecular weight, lipophilicity, or water solubility (ECHA, 2014).



Generally the smaller the molecule the more easily it may be taken up. The molecular weight of the test substance is relatively low with 184.3 g/mol, favouring oral absorption of the compound. However, the absorption of highly lipophilic substances (log Pow >4) may be limited by the inability to dissolve into gastrointestinal fluids and hence make contact with the mucosal surface. Micellar solubilisation by bile salts may enhance absorption, a mechanism which is especially of importance for highly lipophilic substances with log Pow >4 and low water solubility (Aungst and Shen, 1986).

Moreover, the observation of systemic toxicity following exposure by any route is an indication for substance absorption; however, this will not provide any quantitative information.

In an acute oral toxicity study, a total dose of 2000 mg/kg bw of the test substance was administered to 3 male and 3 female rats (2004). No mortality during the observation period and no clinical signs of systemic toxicity were observed. Furthermore, macroscopic post mortem examination did not reveal any abnormalities. In this acute oral toxicity study in rats the LD50 value was determined to be > 2000 mg/kg bw. Additionally, a repeated-dose oral toxicity study in rats was conducted with the test substance (2016). Animals were treated at dose levels of 50, 150 and 500 mg/kg bw/day. Two females were found dead at 500 mg/kg bw/day on Days 3 and 5 post-partum, respectively. Marked thymic lymphoid atrophy (2/2) and mild splenic lymphoid atrophy (2/2) were observed in both dead females at 500 mg/kg bw/day. No mortality was observed in males. Clinical signs such as soiled perineal region and salivation were observed frequently in males and females at 500 mg/kg bw/day.

Based on available data from the acute oral and repeated dose toxicity study, oral toxicity was observed with the test substance and thus absorption of the test substance via the gastrointestinal tract has evidently occurred.


The dermal uptake of liquids and substances in solution is generally expected to be higher than that of dry particles. Molecular weights below 100 g/mol favour dermal uptake, while for those above 500 g/mol the molecule may be too large. Thus, for this molecular weight level of the test substance dermal uptake can be seen to be moderate. The substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Therefore if the water solubility is between 1-100 mg/L, dermal uptake is considered to be low to moderate. For substances with og Powabove 4 the rate of penetration may be limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high.

The dermal permeability constant Kp of the substance was estimated to be 0.122 cm/h using DermwinTM(v.2.01) and taking into account a determined log Pow of 4.4 and the molecular weight of 184.3 g/mol. Thus the absorption of the test substance is anticipated to be moderate and assumed to be 50%.



Any lipophilic compound may be taken up by micellular solubilisation but this mechanism may be of particular importance for highly lipophilic compounds (log Pow >4) (ECHA, 2014).

However, the test substance has a low vapour pressure of 36.87 Pa at 20°C. Therefore, under normal use and handling conditions, inhalation exposure and thus availability for respiratory absorption of the substance in the form of vapour can be considered negligible.


Distribution and Accumulation

No data were found regarding the distribution. Distribution of a compound within the body depends on the physico-chemical properties of the substance; especially the molecular weight, the lipophilic character and the water solubility. In general, the smaller the molecule, the wider is the distribution. If the molecule is lipophilic (log Pow >0), it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues (ECHA, 2014).

Thus, due to the small molecular weight(184.3 g/mol)and a lipophilic character a wider distribution is assumed and a distribution into cells and the intracellular concentration may be higher than the extracellular concentration particular in fatty tissue. Lipophilic substances will tend to concentrate in adipose tissue and depending on the conditions of exposure may accumulate. If the interval between exposures is less than 4 times the whole body half-life of the substance then there is the potential for the substance to accumulate. It is generally the case that substances with high log Pow values have long biological half-lives. On this basis, daily exposure to a substance with a log Pow value of around 4 or higher could result in a build up of that substance within the body. Substances with log Pow values of 3 or less would be unlikely to accumulate with the repeated intermittent exposure patterns normally encountered in the workplace but may accumulate if exposures are continuous. Once exposure to the substance stops, the substance will be gradually eliminated at a rate dependent on the half-life of the substance. If fat reserves are mobilized more rapidly than normal, e.g. if an individual or animal is under stress or during lactation there is the potential for large quantities of the parent compound to be released into the blood (ECHA, 2014). Since no experimental data are available a bioaccumulation potential is assumed.


No data are available regarding metabolism. Prediction of compound metabolism based on physicochemical data is very difficult. Structure information gives some but no certain clue on reactions occurring in vivo. The potential metabolites following enzymatic metabolism were predicted using the QSAR OECD toolbox (v3.3, OECD, 2014). This QSAR tool predicts which metabolites may result from enzymatic activity in the liver and in the skin, and by intestinal bacteria in the gastrointestinal tract. 12 hepatic and 4 dermal metabolites were predicted for the test substance, respectively. Primarily, hydrolysis of the substance to 3,3,5-trimethylcyclohexanol and acetic acid may occur in the liver and skin. In general, the hydroxyl groups make the substances more water-soluble and susceptible to metabolism by phase II-enzymes. Up to 86 metabolites were predicted to result from all kinds of microbiological metabolism for the test substance. Most of the metabolites were found to be a consequence of the degradation of the molecule. There was no evidence for differences in genotoxic potencies due to metabolic changes in in vitro genotoxicity tests. The studies performed on genotoxicity (Ames test and HPRT test and chromosome aberration test in mammalian cells in vitro) were negative, with and without metabolic activation (2013, 2015, 2015).


The major routes of excretion for substances from the systemic circulation are the urine and/or the faeces (via bile and directly from the GI mucosa).Only limited conclusions on excretion of a compound can be drawn based on physico-chemical data.Low molecular weight (below 300 g/mol in rat), good water solubility, and ionization of the molecule at the pH of urine are characteristics favourable for urinary excretion.Due to metabolic changes, the finally excreted compound may have few or none of the physicochemical properties of the parent compound. In addition, conjugation of the substance may lead to very different molecular weights of the final product. Thus based on the available data no final conclusion on the excretion route is possible.



Aungst,B. and Shen,D.D. (1986) Gastrointestinal absorption of toxic agents. In Rozman,K.K. and Hanninen,O. (eds.) Gastrointestinal Toxicology. Elsevier, New York as cited in ECHA (2014), R.7c

ECHA (2014): Guidance on information requirements and chemical safety assessment – Chapter 7c: Endpoint specific guidance. European Chemicals Agency, Helsinki